Neuroinflammation and Memory: The Role of Prostaglandins

Neuroinflammation is a complex response to brain injury involving the activation of glia, release of inflammatory mediators within the brain, and recruitment of peripheral immune cells. Interestingly, memory deficits have been observed following many inflammatory states including infection, traumatic brain injury (TBI), normal aging, and Alzheimer’s disease (AD). Prostaglandins (PGs), a class of lipid mediators which can have inflammatory actions, are upregulated by these inflammatory challenges and can impair memory. In this paper, we critically review the success of nonsteroidal anti-inflammatory drugs, which prevent the formation of PGs, in preventing neuroinflammation-induced memory deficits following lipopolysaccharide injection, TBI, aging, and experimental models of AD in rodents and propose a mechanism by which PGs could disrupt memory formation.     

Preferential increase in the hippocampal synaptic vesicle protein 2A (SV2A) by pentylenetetrazole kindling

The present study evaluated the expressional levels of synaptic vesicle protein 2A (SV2A) and other secretary machinery proteins (i.e., soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, Munc18-1, N-ethylmaleimide-sensitive factor (NSF) and soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP)) in a pentylenetetrazole (PTZ) kindling model. Repeated administration of sub-convulsive PTZ (40 mg/kg, i.p.) progressively increased seizure susceptibility in mice and consistently induced clonic seizures in most animals tested at 15 days after the treatment. Western blot analysis revealed that, among the secretary machinery proteins examined, hippocampal SV2A was selectively elevated by PTZ kindling. PTZ kindling-induced SV2A expression appeared region-specific and the SV2A levels in the cerebral cortex or cerebellum were unaltered. In addition, SV2A expression by PTZ kindling was prominent in the hilar region of the dentate gyrus (DG) where GABAergic interneurons are located, but not in other hippocampal regions (e.g., the stratum lucidum of the CA3 and synaptic layers surrounding CA1 or CA3 pyramidal neurons). These findings suggest that PTZ kindling preferentially elevates SV2A expression in the hippocampus probably as a compensatory mechanism to activate the inhibitory neurotransmission.     

Impairment of long-term depression induced by chronic brain inflammation in rats

Although deficits in synaptic plasticity have been identified in aged or neuroinflamed animals with memory impairments, few studies have examined the cellular basis of plasticity in such animals. Here, we examined whether chronic neuroinflammation altered long-term depression (LTD) and studied the underlying mechanism of LTD impairment by neuroinflammation. Chronic neuroinflammation was induced by administration of lipopolysaccharide (LPS) to the fourth ventricle. Excitatory postsynaptic potentials were recorded extracellularly in the rat hippocampal CA1 area to examine alterations in synaptic plasticity. Chronic administration of LPS induced remarkable memory impairment in the Morris water maze test. N-methyl-d-aspartate receptor (NMDAR)-dependent LTD was almost absent in LPS-infused animals. The AMPA receptor (AMPAR)-mediated synaptic response was reduced in the LPS-infused group. These results suggest that reduction in NMDAR-dependent LTD might arise because of alterations in postsynaptic AMPARs as well as NMDARs and that such changes may be present in mild and early forms of Alzheimer-type dementia.     

Sex and estrous cycle-dependent differences in glial fibrillary acidic protein immunoreactivity in the adult rat hippocampus

Sex differences in the morphology and function of the hippocampus have been reported in several species, but it is unknown whether a sexual dimorphism exists in glial fibrillary acidic protein (GFAP) expression in the rat hippocampus. We analyzed GFAP immunoreactivity in the hippocampus of intact adult male rats as well as in females during diestrus and proestrus phases of the estrous cycle. We found that in CA1, CA3, and dentate gyrus, GFAP immunoreactivity was higher in proestrus females as compared with males and diestrus females. In CA1, a similar GFAP immunoreactivity was found in males and in diestrus females, but in dentate gyrus, males presented the lowest GFAP content. Interestingly, differences in astrocyte morphology were also found. Rounded cells with numerous and short processes were mainly observed in the hippocampus during proestrus whereas cells with stellate shape with few and long processes were present in the hippocampus of males and diestrus females. The marked sex and estrous cycle-dependent differences in GFAP immunoreactivity density and in astrocyte number and morphology found in the rat hippocampus, suggest the involvement of sex steroid hormones in the sexually dimorphic functions of the hippocampus, and in the change in its activity during the estrous cycle.     

慢性复合应激对大鼠学习和记忆及海马神经元神经颗粒素表达的影响

目的探讨慢性复合应激对大鼠学习和记忆功能及海马内神经元神经颗粒素(neurogranin,Ng)表达的影响。方法成年雄性Wistar大鼠随机分为对照组和复合应激组,复合应激组动物每天无规律交替暴露于复合应激原环境中,为期6周。应激结束后,用Morris水迷宫测试大鼠空间学习和记忆成绩,同时用免疫组织化学方法观察海马各亚区Ng表达的变化,并用RT-PCR技术分析各组大鼠海马Ng mRNA水平的变化。结果Morris水迷宫测试显示,应激组动物寻找隐蔽平台潜伏期明显短于对照组(P<0.05);应激组大鼠海马DG和CA3区Ng的蛋白表达水平明显高于对照组(P<0.05),而两组海马CA1区的Ng的免疫反应性无明显差别;与对照组相比,应激组动物的Ng mRNA水平亦明显上调(P<0.05)。结论慢性复合性应激大鼠的学习与记忆能力增强;Ng在海马中的表达和Ng mRNA转录水平增高,提示Ng参与了该增强机制。     

褪黑素对谷氨酸钠致痫大鼠海马5-羟色胺水平的影响

目的观察褪黑素(Melatonin,MT)对谷氨酸钠(Glutamate,Glu)致痫大鼠海马5-羟色胺(5-hydroxytryptamine,5-HT)水平的影响,研究其抑制癫痫的作用机制。方法40只健康雄性SD大鼠随机分为4组(每组10只),分别为生理盐水对照组(NS组);谷氨酸钠致痫组(Glu组);褪黑素 谷氨酸钠组(MT Glu组);Luzidole 褪黑素 谷氨酸钠组(Luz MT Glu组)。观察并记录大鼠行为学及脑电图改变,用免疫组织化学方法检测大鼠海马内5-HT含量变化。结果行为学观察和EEG显示,NS组无痫样发作和痫样放电,Glu组和Luz MT Glu组痫样发作重(Ⅲ-Ⅴ级),脑电图显示频发高幅的痫样波,TM Glu组无或仅有轻微发作(0-Ⅱ级),脑电图上无或偶见散在单个微小痫样波;免疫组织化学分析结果显示,Glu组和Luz MT Glu组大鼠海马内5-HT含量与对照组比较均减少,差异性明显(P<0.05),MT Glu组较Glu组和Luz MT Glu组5-HT含量升高,差异性明显(P<0.05)。结论MT对谷氨酸钠致痫大鼠痫样发作程度、痫样放电有抑制作用,其机制之一是经由其特异性的膜受体,通过某种机制增强5-HT作用,进而发挥抑痫效应。     

穹窿切断后海马神经元GR表达变化的研究

目的实施大鼠穹窿切断术研究海马神经元核受体GR(glucocorticoidreceptor糖皮质激素受体)表达的变化。方法建立大鼠穹窿切断模型,于穹窿切断术后0、4、7、10d取材;同时取材假手术组(非穹窿切断术)作为对照,应用免疫组化、WesternBlotting方法分别进行各组海马神经元GR表达变化的观察及定量检测。结果穹窿切断7d后,免疫组化和WesternBlotting结果显示海马神经元GR表达下调,10d下调更为显著。结论穹窿切断后,海马GR表达下调,提示可能减弱海马对HPA轴的抑制。     

Acquisition of Contextual Discrimination Involves the Appearance of a RAS-GRF1/p38 Mitogen-activated Protein (MAP) Kinase-mediated Signaling Pathway That Promotes Long Term Potentiation (LTP)

RAS-GRF1 is a guanine nucleotide exchange factor with the ability to activate RAS and RAC GTPases in response to elevated calcium levels. We previously showed that beginning at 1 month of age, RAS-GRF1 mediates NMDA-type glutamate receptor (NMDAR)-induction of long term depression in the CA1 region of the hippocampus of mice. Here we show that beginning at 2 months of age, when mice first acquire the ability to discriminate between closely related contexts, RAS-GRF1 begins to contribute to the induction of long term potentiation (LTP) in the CA1 hippocampus by mediating the action of calcium-permeable, AMPA-type glutamate receptors (CP-AMPARs). Surprisingly, LTP induction by CP-AMPARs through RAS-GRF1 occurs via activation of p38 MAP kinase rather than ERK MAP kinase, which has more frequently been linked to LTP. Moreover, contextual discrimination is blocked by knockdown of Ras-Grf1 expression specifically in the CA1 hippocampus, infusion of a p38 MAP kinase inhibitor into the CA1 hippocampus, or the injection of an inhibitor of CP-AMPARs. These findings implicate the CA1 hippocampus in the developmentally dependent capacity to distinguish closely related contexts through the appearance of a novel LTP-supporting signaling pathway.